Tuberculous Osteitis Research Articles

Difficulties in the diagnosis of spinal tuberculosis (clinical observation)

Neurological disorders are widely recognized as the most frequent and dangerous complication of neglected forms of spinal tuberculosis, typically leading to disability. Since tuberculous spondylitis remains free from pathognomonic clinical symptoms, the disease should be suspected in case of ineffective treatment of a non-tuberculous disease with a particular form of spinal tuberculosis to be behind. The diagnostic algorithm, being implemented from the initial stage of tuberculous osteitis formation, involves timely anti-tuberculosis treatment and correct management of patients, thereby making the basis for preventing the neurological disorders and disability of patients. The presented clinical cases indicate the advantage of an integrated approach in the diagnosis of this pathology in terms of establishing the tuberculous etiology of spondylitis.

Effects of a single introduction of pamidronate on intact bone under the conditions of the experimental model of the treatment of tuberculosis ostitis

BACKGROUND: Information about the features of intact bone tissue of the contralateral segment in the treatment of tuberculous osteitis is absent in the literature.
 AIM: Study of the features of intact bone tissue in the conditions of complex treatment of experimental tuberculous osteitis.
 MATERIALS AND METHODS: On an experimental model of tuberculous osteitis of the condyle of the right femur (Mycobacterium tuberculosis H37Rv) in 21 rabbits, the morphometric characteristics of the contralateral femurs, representatively selected from 4 groups, were studied: group (control) who did not receive either surgical or medical treatment; groups 24 radical surgical removal of the focus, supplemented: No. 2 antituberculosis therapy, group 3 antituberculosis therapy and a single injection of bisphosphonates (pamidronate), group 4 a single injection of bisphosphonates. In autopsy material studied: the area of bone tissue, the thickness of bone beams, the number of osteoblasts, osteocytes, osteoclasts and the proportion of their active forms.
 RESULTS: The following features were revealed in intact samples of different groups: group 1 the minimum area of bone tissue and the thickness of the beams, the maximum number of osteoblasts, including active ones, the average number of osteocytes; groups 2 and 3 average values of the area and thickness of bone beams, the average number of osteoblasts, the pool of osteocytes is represented mainly by inactive cells; groups 3 and 4 the minimum value of active osteoblasts; group 4 the maximum thickness of the bone beams, a greater total number of osteoblasts and osteocytes. No osteoclasts were found in any group.
 CONCLUSIONS: Different ratios of bone tissue area, thickness of bone beams, and osteoforming cellular elements in animals receiving different treatment indicate both the systemic effect of a specific process and the drug effect of anti-tuberculosis drugs and bisphosphonates on uninfected bones.

Применение бисфосфонатов при экспериментальном туберкулезном остите: КТ-визуализация

Introduction The complex treatment of osteoarticular tuberculosis is based on combination of anti-tuberculosis therapy, complete (radical) removal of involved bone and restoration of the supporting and motor function of the affected musculoskeletal segment. Inhibited activity of osteoclasts involved in osteoresorption as one of the mechanisms of reparative osteoregeneration can be involved in regulation of bone formation after radical reconstructive surgery. The objective was to explore CT signs of osteoregeneration due to multimodal treatment of experimental tuberculous osteitis with use of bisphosphonates as targeted inhibitors of osteoclasts. Material and methods An experimental study was carried out on 21 mature male Chinchilla rabbits. The first stage included bone tuberculosis simulated in the medial condyle of the right femur using invasive local infection with M. tuberculosis strains H37Rv, a virulent reference laboratory strain. Pathological focus was resected and bone graft used at the second stage. Animals receiving antituberculosis therapy (ATT), ATT and bisphosphonates (BP) and BP only were divided into three groups at the third stage. Animals were sacrificed at 3 and 6 months of surgical treatment at the fourth stage. Autopsy implantation zone, bone of the contralateral condyle and intact femur were quantitatively and qualitatively assessed using micro-CT imaging. Results Positive dynamics in bone restoration was seen in the groups. ATT group showed complete lysis of the implant with bone cavities identified and no bone restoration in half of the cases seen at 6 months. Rabbits treated with BP demonstrated absence of complete lysis of the implant and CT signs of ingrowth of bone trabeculae. CT signs of maximum osteoregeneration were noted in the group of isolated BP therapy. Discussion The use of bisphosphonates can prevent lysis of grafts preserving the osteoconductive properties and facilitating formation of new bone. Conclusion Targeted osteoclast inhibitors can be safety and efficaciously used in the complex treatment of focal infectious skeletal lesions and be recommended as a potential component of pathogenetic therapy in the postoperative treatment of infectious (tuberculous) skeletal lesions.

Olecranon Bone Tumor Complicated by Ulnar Nerve Paresis Revealing Tuberculous Osteitis—About a Case

Introduction: The localization of bone tuberculosis at the level of the olecranon is rare and can pose a problem of differential diagnosis with a tumoral affection. Only the biopsy allows the diagnosis of certainty. The goal was to report our first case to do a review of the literature. Clinical Observation: This was a 64-year-old patient who consulted 2 years after the onset of symptoms for swelling and mechanical pain in the left elbow. On clinical examination there was a firm consistent mass measuring 6/4 cm in diameter, not very painful and hot on the posterior surface of the left elbow, accompanied by paresthesias in the territory of the ulnar nerve associated with partial functional impotence of the left forearm with little altered general condition. The X-rays of the left elbow showed extensive bone lysis of the olecranon with fracture of the base of the olecranon. The CT Scan of the elbow performed showed osteolysis of the olecranon with extensive bone reactions at the distal end of the humerus. The biopsy carried out with histological examination concluded with an aspect of tuberculous osteitis and the culture came back sterile. A curettage was performed associated with anti-tuberculosis treatment for 12 months as well as the placement of a posterior splint. The evolution at 9 months was unsatisfactory with persistence of paresis and stiffness of the elbow. Conclusion: Tuberculous osteitis of the olecranon can simulate a malignant tumor with non-specific signs of bone tuberculosis. Only the anatomopathological examination is definitive for the diagnosis. The treatment is multidisciplinary. Orthopedic evolution is difficult to predict.

Morphometric characteristics of bone tissue in the treatment of experimental tuberculous osteitis with anti-tuberculosis drugs and selective inhibitors of bisphosphonates

Introduction. The effect of bisphosphonates on bone recovery after surgical treatment of osteitis has not been fully understood. Aim: To study morphometric features of bone restoration when bisphosphonates are used after the surgical treatment of experimental tuberculous oste-itis. Material and methods. Experimental model of TB osteitis of distal femur was produced in 21 sexually ma-ture chinchilla male rabbits of distal epimetaphys of fem-oral bone. After resection of the locus and osteoplasty, 3 study arms have been formed depending on the medica-tion therapy: anti-TB drugs only, anti-TB drugs + bisphos-phonates (BF) and BF only. After the end of experiment, 3 and 5 months after surgery, material was harvested in autopsy and histological sections 3–5 microns thick were morphometrically studied on the basis of digital images of the preparations. Results. 3 months after the opera-tion, a greater thickness of the bone rods was noted in the group of rabbits treated with anti-TB drugs + BF, after 6 months — in those treated with BF only (p<0.001). In all the studied groups, relief of specific TB inflammation was achieved in 50–75% of cases 6 months after surgical treatment. Conclusions: The use of BF in the treatment of experimental tuberculous osteitis does not impact the frequency of detection and the area of specific inflamma-tion, while providing the greatest thickness of the bone rods at 3 and 6 months after surgical treatment.

Primary patella tuberculosis mimicking pre-patellar bursitis: A case report and review of the literature.

Introduction and importanceThe Patella is very rare site for tuberculosis (TB). The knee is the third most common site for skeletal TB. The incidence of patella TB being 0.09 to 0.15%.Case presentationWe report a case of primary tuberculous osteitis isolated from the patella. The complaint was a mixed knee pain without notion of trauma. The CT showed a large osteolysis of the upper half of the patella. The diagnosis was established on the histological study after biopsy. The patient was operated by a medial approach without arthrotomy and the pathological tissue was resected and curetted. Complementary anti-bacillary antibiotic treatment was administered for 12 months. At the last clinical control, the knee was free and painless, and we had no recurrence.Clinical discussionAitken reported the first case in literature in 1933. The initial signs and symptoms are non-specific and sometimes confounded by a coincidental history of trauma. It is difficult to diagnose TB of patella in early stages because there are no constitutional symptoms. Sometimes serological parameters are inconclusive. CT scan can help if the osteolysis contained a central bone sequestration, bordered by peripheral sclerosis. Confirmation of patellar tuberculosis is made on biopsy.ConclusionThe tuberculous localization in the patella is rare and it can pose a problem of differential diagnosis with other affections, in particular infectious and tumors. It should always be kept in mind, especially in the face of a picture of pre-patellar bursitis which progresses slowly and whose biological inflammatory syndrome is not straightforward.

Ten years follow up of a chronic tubercular osteomyelitis of the proximal tibia in infancy

<p class="Default">Primary tuberculous osteomyelitis accounts for less than 10% of extra pulmonary tuberculosis in childhood.In about 50% of the patients, the vertebrae are the sites of skeletal involvement. Solitary bone TB is rare in infancy and has non specific findings and can be misdiagnosed easily. A 12 month old infant, presented with fever, pain, swelling in left knee, difficulty in moving left lower limb and inability to bear weight for 15 days at Nizam's institute of medical sciences, Hyderabad, in 2010. She was managed conservatively with injectable antibiotics, initially. After 15 days fever and swelling recurred. A biopsy was performed which showed plenty of polymorphs. A month later with second recurrence she was operated by means of debridement and curettage. Subsequent biopsy and culture revealed active <em>Mycobacterial tuberculous</em> infection. Anti-tubercular treatment titrated to her body weight was administered for 12 months and patient was followed up. The patient’s general condition improved with betterment in laboratory parameters, resolution of the lesion, without any sequelae. Upon a close follow up of 10 years (2010-2020), no residual deformity was noted and excellent clinical outcome achieved. Skeletal TB without spinal involvement in children is rare and it does not have any pathognomonic radiographic or clinical characteristics. Physis can heal gradually and full range of motion of the adjacent joints can be maintained. Tuberculosis should be an essential differential diagnosis while addressing cases with similar presentation in endemic regions like India. As clinical and radiological findings may be indistinguishable from malignant disease, tuberculous osteitis should be excluded in infants presenting with undiagnosed bone lesions despite been vaccinated with Bacille Calmette Guerin at birth.</p>

Bacillus Calmette–Guérin (BCG) vaccine safety surveillance in the Korea Adverse Event Reporting System using the tree-based scan statistic and conventional disproportionality-based algorithms

BackgroundSubstantial variations in the safety profiles of different formulations of the bacillus Calmette–Guérin (BCG) vaccine exist. Therefore, we aimed to detect safety signals of BCG vaccine for intradermal injection (BCG-ID) and percutaneous injection (BCG-PC) in the Korea Adverse Event Reporting System (KAERS). MethodsWe conducted a vaccine safety surveillance study from the adverse events (AEs) reported following BCG vaccine in the Korea Institute of Drug Safety and Risk Management KAERS Database (KIDS-KD) between 2005 and 2017. We used the tree-based scan statistic (TSS) and four disproportionality-based algorithms for signal detection: empirical Bayesian geometric mean; proportional reporting ratio; reporting odds ratio; and information component. The detected signals from each algorithm was compared with the known AEs of BCG vaccine (reference standard) to present positive predictive value (PPV) and area under the receiver operating curve (AUC). ResultsFrom the total of 52,191 vaccine-related AE pairs, 963 AE pairs were reported following the BCG vaccine, in which BCG-ID and –PC accounted for 71.1% and 28.9%, respectively. Overall, 97.2% of AE reports were non-serious; lymphadenopathy (583/963; 50.3%) and injection site discharge (193/963; 20.0%) were the most commonly reported AEs detected by all algorithms. Tuberculous osteitis was reported solely from BCG-PC (15/279; 5.4%), while most of the AEs from BCG-ID were related to injection site complications. The TSS demonstrated the best balance of the performance measures, with PPV and AUC of 66.7% and 63.1%, respectively. ConclusionsTSS was successfully applied in the KAERS to detect safety signals of BCG vaccine. In addition, difference in the safety profiles of BCG-ID and BCG-PC warrants further investigation to confirm our findings. Although TSS performed the best in our study, caution should be taken when interpreting the results owing to the lack of a robust “gold standard” and the relatively small number of reports for data mining.

Influence of the electret electric field on osteoreparation and inflammation in surgical treatment of simulated tuberculous osteitis estimated by morphological and biochemical criteria

Introduction. Recent trends in orthopedic surgery target factors and conditions that affect the destructive process-es in bone tissue and the effectiveness of reconstructive surgery. Electrets based on anodic tantalum oxide with negative external surface charge (hereinafter, “electret”) create a quasi-static long-term electric field in the sur-rounding space. Their implantation in the surgical treat-ment of early stages of degenerative joint diseases is accompanied by pronounced analgesic effect and signi-ficant increase in the quality of life of patients. Objective.To identify the features of osteogenesis and regression of specific inflammation in the surgical treatment of ex-perimental tuberculous osteitis in a constant electric field created by electret. Materials and methods. We studied the processes of osteoreparation and dynamics of the bone tissue specific inflammation activity in 30 rabbits with simulated tuberculous osteitis of the distal (meta-diaphysis) femur. 3 animals were intact (group 1), 6 rab-bits did not receive any therapy after tuberculous oste-itis simulation (group 2), 9 rabbits (group 3) underwent necrectomy and osteoplasty with autograft, 9 rabbits (group 4) underwent necrectomy and electret implanta-tion (with further generation of quasi-static electric field), and 6 animals (group 5) underwent necrectomy, osteo-plasty with autograft and perifocal electret implantation. Animals in groups 3, 4 and 5 received antituberculous therapy. The observation period was 1, 2 and 4 months after the grafting procedure. Bone regeneration and in-flammation regression were assessed with morphologi-cal and biochemical methods (enzymes of the purinergic system — activity of total adenosine deaminase and its isoenzymes, elastase activity, level of acute phase reac-tants: ceruloplasmin, haptoglobin, α1-acid glycoprotein, and albumin). Results. The evolution of tuberculous in-flammation of bone tissue was observed for the control periods in animals with simulated tuberculous osteitis. The analysis of bone tissue reparation and inflammation activity regression showed that only a combination of antituberculosis therapy, necrectomy, osteoplasty with autograft and electret perifocal implantation allowed in 2 months to achieve complete regression of active tuber-culosis and replacement of defect with mature trabec-ular bone. Conclusion. The electret electric field based on anodic tantalum oxide with negative external surface charge accelerates the processes of osteoreparation and reduces the activity of tuberculous inflammation in the surgical treatment of experimental tuberculous osteitis.

Possibilities of differentiation of various processes that cause focal destruction of small and flat bones in children

Purpose of the study. Systematize Rg, CT and MRI semi-otics of destructive processes in flat and spongy bones in children and determine the diagnostic significance of various X-ray signs for differentiating tuberculosis and other destructive processes and the statistical relation-ship between them. Material and methods. 123 children with suspected tuberculous osteitis were selected for the study. Tuberculous osteomyelitis was detected in 80 (65.1%) patients, nonspecific osteomyelitis in 27 (21.9%), non-bacterial osteomyelitis and oncological processes in 8 (6.5%), respectively. Results. Fistulous process is more common in tuberculous osteomyelitis. Temperature rise to febrile numbers — in patients with nonspecific osteo-myelitis. Their combination was found only with tubercu-losis. Tuberculosis was characterized by large (>10 mm), single cavities with a clear contour, with the presence of sequesters. Nonspecific osteomyelitis was characterized by smaller (5–10 mm), single cavities without destroying the cortical closing plate. In case of non-bacterial osteo-myelitis, multiple cavities with a clear contour, with the presence of sequesters, were more oftenly detected. Oncological processes were characterized by swelling of the bone with the presence of periostitis, as well as large single cavities with a clear contour, with sclerotic chan-ges in the surrounding bone tissue. In some cases, a solid component in soft tissues was visualized. Conclusion.The radiological and cli nical picture is often non-specific for the pathology in question, however, the identification of some symptoms makes it possible to suspect a certain pathological process with a certain degree of probability, which ultimately should lead to a shortening of the diag-nostic pause

Structure and Physicochemical Mechanisms of Interaction of Bone Tissue with Titanium Implants in Cases of Tuberculous Osteitis

The structural and physicochemical mechanisms of interaction of bone tissue with titanium implants under conditions of tuberculous osteitis are studied using scanning electron microscopy, X-ray diffraction analysis, IR spectroscopy, and thermal analysis. Physiological regeneration of bone tissue during treatment of tuberculous osteitis is accompanied by an increase in the organic component, embrittlement of the mineral phase of the bone matrix, and its decomposition to fine particles. The presence of titanium implants under physiological conditions contributes to the activation of the synthesis of the apatite phase in the regenerating bone. The primary mechanism of implantation osteogenesis in tuberculous osteitis is the formation of an inorganic phase of hydroxyapatite mainly in the regions of destruction of the titanium alloy.

Структура и физико-химические механизмы взаимодействия костной ткани с титановыми имплантатами в условиях туберкулезного остита

The structure and physicochemical mechanisms of interaction of bone tissue with titanium implants in tuberculous osteitis have been studied by scanning electron microscopy, X-ray phase analysis, IR spectroscopy and thermal analysis methods. It has been found that the physiological regeneration of bone tissue is accompanied by growth of organic components, embrittlement of the mineral phase of the bone matrix, and its fine disintegration during the treatment of tuberculosis osteitis. The presence of titanium implants during a physiologically normal state contributes to the activation of apatite phase synthesis in the regenerating bone. The main mechanism of implantation osteogenesis in tuberculous osteitis is the formation of the inorganic phase of hydroxyapatite mainly in the areas of destruction of the titanium alloy.

Physicochemical Properties and Structure of the Bone Matrix in Simulated Tuberculous Osteitis

The physicochemical properties and structure of the bone matrix are studied in a case of simulated tuberculous osteitis without treatment and after a full course of specific antibacterial therapy. Using X-ray diffraction, infrared spectroscopy, thermal analysis, and scanning electron microscopy, we revealed that tuberculous osteitis causes fine disintegration of the bone matrix due to an increase in nonstoichiometric hydroxyapatite, formation of amorphous calcium phosphates, and a decrease of the organic phase, which is accompanied by embrittlement of the bone matrix. Excessive growth of carbonate-hydroxyapatite crystals of a mixed AB substitution type leads to excessive osteogenesis, accompanied by the uncontrolled growth of bone trabeculae. The presence of “liming” regions in the crystal lattice of hydroxyapatite increases the “binding” properties of the bone matrix in which mycobacteria are immobilized and removed in the composition of detritus.

Физико-химические свойства и структура костного матрикса при смоделированном туберкулезном остите

AbstractThe physicochemical properties and structure of the bone matrix are studied in a case of simulated tuberculous osteitis without treatment and after a full course of specific antibacterial therapy. Using X-ray diffraction, infrared spectroscopy, thermal analysis, and scanning electron microscopy, we revealed that tuberculous osteitis causes fine disintegration of the bone matrix due to an increase in nonstoichiometric hydroxyapatite, formation of amorphous calcium phosphates, and a decrease of the organic phase, which is accompanied by embrittlement of the bone matrix. Excessive growth of carbonate-hydroxyapatite crystals of a mixed AB substitution type leads to excessive osteogenesis, accompanied by the uncontrolled growth of bone trabeculae. The presence of “liming” regions in the crystal lattice of hydroxyapatite increases the “binding” properties of the bone matrix in which mycobacteria are immobilized and removed in the composition of detritus.

Osteitis of the radius following Bacillus Calmette\u2013Gu\xe9rin vaccination at birth: a case report

BackgroundThe Bacillus Calmette–Guérin vaccine, which is used for the prevention of tuberculosis, is considered protective against the severe forms of childhood tuberculosis. However, some serious adverse reactions including osteitis of the long bones can occur.Case presentationWe report a case of an 18-month-old Sudanese girl who presented at the age of 3 months with swelling of her left forearm following Bacillus Calmette–Guérin vaccination administered at birth. Radiological and histological investigations confirmed tuberculous osteitis of the distal radius. She responded very well to antituberculous treatment with complete healing at follow-up visits. To the best of our knowledge this is the first case report of osteitis of the radius following Bacillus Calmette–Guérin vaccination described from Sudan.ConclusionsBacillus Calmette–Guérin osteitis, although rare, should be considered a possible complication of the Bacillus Calmette–Guérin vaccination, and early diagnosis and treatment are essential.

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Background Surgical treatment is essential for patients with tuberculous spondylitis, abscess and compression of the spinal cord. Conservative treatment is practical for patients with tuberculous osteitis uncomplicated with compression of the spinal cord. Objective Make a comparative analysis of surgical treatment produced for pre-spondylitis and post-spondylitis patients with spine tuberculosis. Material and methods Surgical treatment was performed for 17 (28.8 %) patients with tuberculous osteitis and 42 (71.2 %) patients with progressing spondylitis. Debriding resection of tuberculous focus, decompression of the spinal cord, abscess drainage were followed by anterior spine fusion with mesh cages or porous constructs of memory metal nitinol, posterior spondylodesis with self-locking shape memory clamps or transpedicular system. Results Static and dynamic spine function, ability to work were restored in 16 (94.8 %) patients with tuberculous osteitis and 29 (69.1 %) patients with progressing spondylitis. Complications developed in 30.9 % of the patients with progressing spondylitis. Conclusions Application of combined spondylodesis allowed for restoration of static and dynamic function of the spine in 17 cases at 6-month follow-up. Early ambulation of patients with tuberculous osteitis and spondylitis was shown to provide regression of neurological deficit after stabilization of anterior and posterior supporting vertebral column. Surgical treatment combined with chemical therapy at early stages of spine tuberculosis appeared to prevent infection and neurological complications, and considerably reduce rehabilitation period

DIAGNOSTIC IMAGING OF BCG OSTEITIS OF STERNUM IN A CHILD

BCG osteitis is an uncommon complication of the antitubercular vaccination. We review some information about the epidemiology, clinical presentation and diagnostic methods of BCG or tuberculous osteitis of sternum. We report a case of BCG osteitis, that was detected with the multispiral computer tomography. We discurse the diagnostic sings of this post-vaccination complication. The diagnosis was verified by laboratory studies, which allows to confirm the etiology of the process.

Calvarial tuberculosis - a case report

Tuberculosis is an infectious disease caused by acid fast bacilli, Mycobacterium tuberculosis that usually affects the lung although it may affect any organ. Tuberculous osteitis of the cranial bone is known as calvarial tuberculosis. The disease is considered secondary to an active or latent tuberculous lesion elsewhere in the body, but direct spread from orbit, paranasal sinuses and face has also been implicated. Though tuberculosis is endemic in Bangladesh, calvarial tuberculosis is very very rare. We report a case of a female, diabetic, hypertensive, chronic kidney disease(CKD), bronchial asthma patient presented with osteolytic lesion in skull with adjacent subcutaneous swelling. She was eventually diagnosed as calvarial tuberculosis on the basis of positive MTB- PCR from the pus aspirated from the swelling.Bangladesh Crit Care J March 2016; 4 (1): 41-43

The influence of roncoleukin on reparative processes of bone tissue in experimental tuberculous osteitis

The effect of Roncoleukin on the recovery of the bone tissue in plastic operational defects (autobone+OsteoSet-T) on the model of experimental tuberculous osteites in 36 rabbits caused by drug resistant clinical strains of M. tuberculosis was studied. It was conducted a comparative analysis of the results of applying of Roncoleukin (12,5 mg/kg, 5 injections, one every 3 days) with anti-tuberculosis treatment in pre-and post-operative period. Efficacy was assessed in 1 and 6 months of surgical intervention on the phagocytic activity of peritoneal macrophages, X-ray study of plastics area, histological study of bone tissue sections. It was found that the most effective use of Roncoleukin appeared in the postoperative period. The analysis showed that Roncoleukin helped to accelerate the restructuring of plastic material - OsteoSet-T, reducing the prevalence of specific foci of inflammation in the bone tissue and the disappearance of alternative necrotic component; the increase of osteogenesis intensity with the new bone beams formation., as well as the activation of hematopoesis in bone marrow. The intensification of reparative processes in the bone combined with a distinct activation of phagocytosis.

Calvarial Tuberculosis With Intracranial Tuberculomas: A Rare Association

Tuberculosis is an infectious disease caused by the acid-fast bacilli Mycobacterium tuberculosis that usually affect the lungs although it may affect any organ. Though incidence of tuberculosis is on rise especially in third world countries like India, tuberculous osteitis of the cranial bones, also known as calvarial tuberculosis, is an uncommon manifestation of disseminated tuberculosis. Calvarial tuberculosis as primary tubercular infection is very rare and rarer still is its association with tuberculomas. We report a case with multiple osteolytic cranial lesions and tuberculomas without focus of infection elsewhere in the body. doi: http://dx.doi.org/10.4021/jnr210w